Polymorphism of Progesterone: Relative Stabilities of the Orthorhombic Phases I and II Inferred from Topological and Experimental Pressure-Temperature Phase Diagrams

Temperatures and melting enthalpies of orthorhombic Phases I and II of natural progesterone, together with the temperature dependence of their lattice parameters and the specific volume of the melt at ordinary pressure, have been determined. With these results, a topological pressure-temperature (P-T) phase diagram accounting for the thermodynamic relationships between these phases has been constructed by way of the Clapeyron equation. The dependence of the melting temperature on the pressure has also been determined for each phase by high-pressure differential thermal analysis. It was found that, upon increasing the pressure, the melting curves converge to the I-II-liquid triple point (TI-II-liquid = 459.4 K, PI-II-liquid = 149.0 MPa), in close agreement with its topological location. This entails that Phase II should exhibit a stable phase region at higher pressure. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1657-1670, 2009